This is an application for renewal of ongoing Program-project support of research on the regulation of the cardiovascular system. Ten different areas of investigation, each under the leadership of an independent investigator, approaches circulatory research from a unique point of view. These approaches include, 1) the autonomic, 2) spinal, and 3) hypothalamic-brainstem levels of cardiodynamic regulation, 4) cardiac-and hepatic metabolism, 5) mechanical properties of blood vessels, 6) neuroendocrine feedback mechanisms in cardiovascular control, 7) total denervation and reinnervation of the heart, 8) cardiovascular functions in mammalian hibernators, 9) histochemical and ultrastructural studies of the cardiac innervation, and 10) the microcirculation. Transection and reanastomsis of the atria, together with dissection of the adventitia of the aorta and pulmonary artery produces complete cardiac denervation without interrupting the innervation of other thoracic or abdominal organs. Careful surgical dissection of local neural projections should permit selective ("custom") denervation of individual portions of the heart. Electrical stimulation of small cardiac nerves, with local recordings of mechanical and/or electrical activities will be employed to describe their specific distributions. The implications of such local distribution patterns will be explored for evidence of asynchrony and dysrhythmia as well as unequal inotropic, chronotropic and dromotropic responses. The participation of both contractile and elastic elements in smooth muscle of arterial blood vessels are being investigated and described during isometric and isotonic contraction. The participation of the liver and the reticuloendothelial system in the development of hemodynamic and endotoxin shock is being vigorously examined. The possible roles of the kidney and renin-angiotensin systems in the onset and maintenance of hypertension, together with the physiology of the microcirculation and autoregulation of blood vessels will be explored in depth. A colony of hibernating ground squirrels (and woodchucks) is maintained on a twelve month basis, and the hearts, blood and other tissues from hibernating and arousal animals will be studied. Locations and functional properties of cardiac and vasomotor pathways, both efferent and afferent, will be documented.